Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

Abstract

Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

“…Several mechanisms have been hypothesized, including low monoamine levels (2), reduced neuroplasticity through altered glutamate or growth factor signaling (3), impaired neuroendocrine stress response regulation (4), and more recently, altered activity of corticolimbic brain regions driven by altered excitatory and inhibitory neuron function (5, 6). Although interesting insight has emerged from these hypotheses, limited progress has been made in drug development, whereby current treatments remain ineffective in half of treated patients (7).…”

Ketamine and suicidal ideation in depression: Jumping the gun?

“…Interestingly, lanicemine (AZD6765), an NMDA channel blocker with lower propensity to cause psychomimetic effects than ketamine, showed rapid-onset and sustained antidepressant effects [22]. The antidepressant mechanisms of ketamine involving various neurotransmitters, signalling pathways and neurotrophic factors that lead to synaptogenesis and plasticity effects have been extensively reviewed in the recent past [23][24][25][26][27][28][29][30][31][32]. A simplified version of the proposed mechanism that underlies the rapid-onset antidepressant action of ketamine is presented here based on preclinical investigations, which report that NMDA antagonism modulates downstream pathways in rodent brain, especially in prefrontal cortex and hippocampus (Fig.…”

Individual level reliability of PAS-induced neural plasticity

“…Between-subject factors include age (Sale et al, 2007;Müller-Dahlhaus et al, 2008), gender (Tecchio et al, 2008), cortical thickness (Conde et al, 2012;List et al, 2013), and genetic polymorphisms (Kleim et al, 2006;Cheeran et al, 2008;Missitzi et al, 2011). Finally, multiple drugs are reported to alter plasticity responses, such as tianeptine (McEwen and Chattarji, 2004), ketamine (Wang et al, 2015) and fluoxetine (Chollet et al, 2014). A method of assuring reliable individual responses to the PAS intervention would be highly valuable.…”